US5250682A - Process for the preparation of 6-[3-substitutedaminopropionyl]-7-deacetylforskolin derivatives - Google Patents
Process for the preparation of 6-[3-substitutedaminopropionyl]-7-deacetylforskolin derivatives Download PDFInfo
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- US5250682A US5250682A US07/733,812 US73381291A US5250682A US 5250682 A US5250682 A US 5250682A US 73381291 A US73381291 A US 73381291A US 5250682 A US5250682 A US 5250682A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/92—Naphthopyrans; Hydrogenated naphthopyrans
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
Definitions
- the present invention relates to a novel process for the preparation of 6 ⁇ -(3-substitutedaminopropionyl)-7-deacetyl-forskolin derivatives of high pharmacological interest represented by the general formula I, ##STR2## wherein R 1 and R 2 each stands for hydrogen, alkyl, aryl, aralkyl or dialkylaminoalkyl; or
- R 1 and R 2 together with the nitrogen to which they are attached form a heterocycle which may contain an additional heteroatom such as N, O, S and may optionally be substituted at one or more positions by groups such as alkyl, alkoxy, hydroxyl, halogen or aryl and pharmaceutically acceptable salts thereof.
- Such compounds are of high interest especially because of compound NKH-477, a 6 - substitutedaminopropionylforskolin derivative, which is very useful in the treatment of congestive heart failure.
- alkyl stands for a C 1 -C 6 , preferably C 1 -C 4 straight or branched chain such as methyl, ethyl, propyl, isopropyl, n-butyl, tert. butyl or n-pentyl.
- aryl stands for phenyl, optionally substituted with groups such as C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, hydroxyl, halogen such as chlorine or fluorine, nitro, cyano or trifluoromethyl.
- aralkyl stands for benzyl, wherein phenyl has the same meanings defined above.
- dialkylaminoalkyl stands for groups such as for example dimethylaminopropyl or diethylaminobutyl.
- heterocycle stands for groups such as e.g. morpholino, piperidino, pyrrolidino, piperazino or homopiperidino, which may be substituted preferably by C 1 -C 4 -alkyl.
- Pharmaceutically acceptable salts means salts of inorganic and organic acids such as hydrochloric acid, hydrobromic acid, sulphonic acid, phosphoric acid, formic acid, acetic acid, maleic acid, citric acid, tartaric acid, lactic acid, methane-sulphonic acid.
- compounds of the formula I can be prepared from 7-deacetylforskolin II, ##STR4## in a one-pot reaction sequence, by treatment of II (1 eq) with a 3-halo-propionyl halide (1.1-3.0 eq) in the presence of an organic base such as e.g. pyridine, diisopropyl ethylamine or triethylamine, preferably triethylamine, (4-50 eq),in an aprotic solvent such as e.g.
- the present invention describes a process for preparation of 6 ⁇ -[3-dimethylaminopropionyl]-7-deacetylforskolin which comprises treatment of 3-chloropropionylchloride (1.1-3.0 eq) with 7-deacetylforskolin (1 eq) of the formula II in the presence of an organic base such as triethylamine (4-50 eq) in an aprotic solvent such as toluene at temperatures ranging from about 0° C. at the beginning of the reaction to ambient temperature at the end of the reaction for a period of about 1.5 to 3 hours, preferably 1.5 hours, or a temperature range of about 0°-120° C.
- an organic base such as triethylamine (4-50 eq
- aprotic solvent such as toluene
- 3-Chloropropionylchloride (1 ml) was added to a mixture of 7-deacetylforskolin (2.0 g), toluene (100 ml) and dry triethylamine (4 ml) at 0° C. The reaction mixture was stirred at ambient temperature to 120° C. for 1.5 hrs. and concentrated under vacuo.
Abstract
Process for the manufacture of 6β-(3-substituted amino)propionyloxy-7-deacetyl-forskolin derivatives of the general formula ##STR1##
Description
The present invention relates to a novel process for the preparation of 6β-(3-substitutedaminopropionyl)-7-deacetyl-forskolin derivatives of high pharmacological interest represented by the general formula I, ##STR2## wherein R1 and R2 each stands for hydrogen, alkyl, aryl, aralkyl or dialkylaminoalkyl; or
R1 and R2 together with the nitrogen to which they are attached form a heterocycle which may contain an additional heteroatom such as N, O, S and may optionally be substituted at one or more positions by groups such as alkyl, alkoxy, hydroxyl, halogen or aryl and pharmaceutically acceptable salts thereof. Such compounds are of high interest especially because of compound NKH-477, a 6 - substitutedaminopropionylforskolin derivative, which is very useful in the treatment of congestive heart failure.
The term alkyl stands for a C1 -C6, preferably C1 -C4 straight or branched chain such as methyl, ethyl, propyl, isopropyl, n-butyl, tert. butyl or n-pentyl.
The term aryl stands for phenyl, optionally substituted with groups such as C1 -C4 -alkyl, C1 -C4 -alkoxy, hydroxyl, halogen such as chlorine or fluorine, nitro, cyano or trifluoromethyl.
The term aralkyl stands for benzyl, wherein phenyl has the same meanings defined above.
The term dialkylaminoalkyl stands for groups such as for example dimethylaminopropyl or diethylaminobutyl.
The term heterocycle stands for groups such as e.g. morpholino, piperidino, pyrrolidino, piperazino or homopiperidino, which may be substituted preferably by C1 -C4 -alkyl.
Pharmaceutically acceptable salts means salts of inorganic and organic acids such as hydrochloric acid, hydrobromic acid, sulphonic acid, phosphoric acid, formic acid, acetic acid, maleic acid, citric acid, tartaric acid, lactic acid, methane-sulphonic acid.
Compounds of the formula I belong to the series of water-soluble aminoacyl forskolin derivatives which display potent pharmacological properties. They are the subject of different patent applications and publications viz. EP application No. 0222413, E.P. Application No. 0193132; Indian Patent No. 163242, Ger. Appl. No. P 3535086.5; Indian Pat. Appl. No. 164675, Ger. Pat. appln. No. 3623300-5; J. P. Appln. No. 159638; Ind. Pat. Appln. No. 238/BOM/87, Ger. Pat. Appl. No. 3737353.6, Mol. Pharmacol., 32, 133 (1987). Processes for their preparation can be summarised as below: ##STR3##
As the sequences show, compounds of formula I are prepared
(a) directly, without the use of protecting groups at the 1-OH or 1-OH/9-OH positions, which results into the formation of formula I along with 1, 6-diacylated compound. Separation of these compounds was tedious.
(b) by protecting the 1-OH group with a protecting group such as t-butyldimethylsilyl or methoxyethoxymethyl, and removing the protecting group at an appropriate stage (Patent Nos. E.P. 0193132 and E.P. 0222413).
(c) by protecting the 1-OH group together with 9-OH group with groups such as carbonyl (C═O), thiocarbonyl (C═S), CHNRR', and removing the 1,9-protecting group at an appropriate stage (Patent No. E.P. 0193132).
All the processes of the prior art have several disadvantages:
(a) Those processes in which direct acylation of the 7-OH group is followed by migration to 6-position. These involve 2-3 steps and also use of anhydrous amine.
(b) Those processes in which protection of 1-OH and/or 9-OH is mentioned, the number of steps is increased i.e. initial protection and then in the last step deprotection of the 1-OH and/or 9-OH group.
Inventiveness and Detailed Description of the Present Invention
In the present invention, it has now been surprisingly found that compounds of the formula I can be prepared from 7-deacetylforskolin II, ##STR4## in a one-pot reaction sequence, by treatment of II (1 eq) with a 3-halo-propionyl halide (1.1-3.0 eq) in the presence of an organic base such as e.g. pyridine, diisopropyl ethylamine or triethylamine, preferably triethylamine, (4-50 eq),in an aprotic solvent such as e.g. chloroform, dichloromethane, toluene or xylene, preferably toluene, at a temperature of about 0°-1200° C., subsequently concentrating the reaction mixture under vacuo to dryness, addition of a water miscible solvent such as e.g. Tetrahydrofuran, dioxane or acetonitrile preferably acetonitrile and water, and an aqueous base such as e.g. aqueous KOH, aqueous NAOH (1-5 eq), followed by addition of an appropriate amine or an aqueous solution of an appropriate amine in excess of about 1 eq, for example an aqueous solution of e.g. dimethylamine, piperidine, morpholine or N-methylpiperazine, leading to the desired 6β-(3-substituted amino propionyl)-7-deacetyl-forskolin derivatives. These derivatives can be optionally converted to pharmaceutically acceptable salts.
The inventiveness of the above process for the preparation of 6β-[3-substitutedaminopropionyl]-7-deacetyl-forskolin derivatives lies in (a) no step being needed for protection of hydroxy groups, (b) a one-pot reaction process, thus rendering it simple and economical and (c) use of simple, commercially available reagents, such as aqueous dimethylamine. It could not be expected, that especially steps (a) and (b) would be practicable.
The above conditions were developed with a view to run the process in good yield, with low costs and with minimized industrial hazards.
More specifically, the present invention describes a process for preparation of 6β-[3-dimethylaminopropionyl]-7-deacetylforskolin which comprises treatment of 3-chloropropionylchloride (1.1-3.0 eq) with 7-deacetylforskolin (1 eq) of the formula II in the presence of an organic base such as triethylamine (4-50 eq) in an aprotic solvent such as toluene at temperatures ranging from about 0° C. at the beginning of the reaction to ambient temperature at the end of the reaction for a period of about 1.5 to 3 hours, preferably 1.5 hours, or a temperature range of about 0°-120° C. throughout the reaction period, subsequent concentration in vacuo of the reaction mixture to dryness, followed by addition to the residue of aqueous acetonitrile preferably in the ratio of acetonitrile:water of 8:7 and aqueous sodium hydroxide preierably of 1N concentration, stirring at ambient temperatures for a period from about 24 hours to 80 hours preferably 72 hours and finally addition of the desired amine (anhydrous or aq. solution) to the reaction mixture and continuing the stirring for an additional two to four hours to obtain the desired product.
The following examples are provided to serve only as an illustration of how the process is to be worked, without being exclusive of other compounds of the invention that may be so prepared.
3-Chloropropionylchloride (1 ml) was added to a mixture of 7-deacetylforskolin (2.0 g), toluene (100 ml) and dry triethylamine (4 ml) at 0° C. The reaction mixture was stirred at ambient temperature to 120° C. for 1.5 hrs. and concentrated under vacuo.
The residue was taken in acetonitrile:water (8:7, 150 ml), and 1N sodiumhydroxide (17 ml) was added to the above solution. The reaction mixture was stirred-at ambient temperature for 3 days and aqueous dimethylamine (30-40%, 40 ml) was added. The reaction mixture was further stirred for 2 hours at ambient temperature and extracted with ethyl acetate. The organic layer was washed, dried over anhydrous sodium sulphate and concentrated. The residue on purification by chromatography yielded the desired compound. Yield˜1.4 g. m.p. 140°-142° C.
Similarly, the following compounds were prepared by using the appropriate amine.
2. 6β-(3-N-methylpiperazinopropionyl)-7-deacetylforskolin. m.p. 187°-189° C.
3. 6β-(3-piperidinopropionyl)-7-deacetylforskolin. m.p. 149°-150° C.
4. 6β-(3-morpholinopropionyl)-7-deacetylforskolin. m.p. 188°-190° C.
TABLE 1
______________________________________
PMR DATA FOR THE ABOVE WORKINGS EXAMPLES
______________________________________
1. NR.sub.1 R.sub.2 = NMe.sub.2
PMR (CDCl.sub.3): δ =
6.08(d of d, J.sub.cis =10.8Hz, J.sub.trans =
18Hz, vinylic- .sub.-- H), 5.9(d of d, J.sub.6,7 =
4.5Hz, J.sub.5,6 =3Hz, 6-C .sub.-- H), 5.18(d of
d, J.sub.trans =18Hz, J.sub.gem =2Hz,
vinylic- .sub.-- H), 4.94(d of d, J.sub.cis =10.8
Hz, J.sub.gem =2Hz, vinylic- .sub.-- H), 4.56(bs,
1-C .sub.-- H), 4.19(d, J=4.5Hz, 7-C .sub.-- H), 3.32
(d, J.sub.gem =17Hz, 12-CH), 2.7-2.2(m,
COC .sub.-- H.sub.2, NCH2, 12-C .sub.-- H), 2.3(s,
NC .sub.-- H.sub.3), 1.6, 1.46, 1.42, 1.14,
1.0(s, 5×C .sub.-- H.sub. 3).
##STR5##
PMR (CDCl.sub.3): δ =
6.08(d of d, J.sub.cis =10.8Hz, J.sub.trans =
18Hz, vinylic- .sub.-- H), 5.9(d of d, J.sub.6,7 =
4.5Hz, J.sub.5,6 =3Hz, 6-C .sub.-- H), 5.14(d of
d, J.sub.trans =18Hz, J.sub.gem =2Hz,
vinylic- .sub.-- H), 4.94(d of d, J.sub.cis =10.8Hz,
J.sub.gem =2Hz, vinylic- .sub.-- H), 4.58(bs,
1-C .sub.-- H), 4.19(d, J.sub.gem =4.5Hz, 7-C .sub.-- H),
3.2(d, J.sub.gem =17Hz, 12-C .sub.-- H), 2.7-2.2
(m, COC .sub.-- H.sub.2, NC .sub.-- H.sub.2, 12-C .sub.--
H), 2.3(s,
NC .sub.-- H.sub.3), 1.56, 1.42, 1.4, 1.1, 0.96(s,
5×C .sub.-- H.sub.3).
##STR6##
PMR (CDCl.sub.3): δ =
6.08(d of d, J.sub.cis =10Hz, J.sub.trans =
17Hz, vinylic- .sub.-- H), 5.9(d of d, J.sub.6,7 =
4.5Hz, J.sub.5,6 =3Hz, 6-C .sub.-- H), 5.14(d of
d, J.sub.trans =17Hz, J.sub.gem =2Hz,
vinylic- .sub.-- H), 4.94(d of d, J.sub.cis =10Hz,
J.sub.gem =2Hz, vinylic- .sub.-- H), 4.58(bs,
1-C .sub.-- H), 4.18(bs, collapse to d on D.sub.2 O
addition J=4.5Hz, 7-C .sub.-- H), 3.22(d,
J.sub.gem =17Hz, 12-C .sub.-- H), 2.8-2.08(m,
COCH.sub.2, NCH.sub.2, 12-C .sub.-- H), 1.6, 1.44, 1.4,
1.1, 0.96(s, 5×C .sub.-- H.sub.3).
##STR7##
PMR (CDCl.sub.3): δ =
6.08(d of d, J.sub.cis =10Hz, J.sub.trans =
17Hz, vinylic- .sub.-- H), 5.9(d of d, J.sub.6.7 =
4.5Hz, J.sub.5,6 =3Hz, 6-C .sub.-- H), 5.16(d of
d, J.sub.trans =17Hz, J.sub.gem =2Hz,
vinylic- .sub.-- H) 4.94(d of d, J.sub.cis =10Hz,
J.sub.gem =2Hz, vinylic- .sub.-- H), 4.6(bs,
1-C .sub.-- H), 4.2(d of d, J.sub.6,7 =4.5Hz,
J.sub.7,OH =6Hz, collapse to d, J=4.5
Hz, 7C .sub.-- H), 3.7(t, J=5.4Hz, OC .sub.-- H.sub.2),
3.02(d, J.sub.gem =17Hz, 12-C .sub.-- H), 2.88-2.2
(m, COC .sub.-- H.sub.2, NC .sub.-- H.sub.2, 12-C .sub. --
H), 1.6, 1.42,
1.4, 1.1, 0.98(s, 5×C .sub.-- H.sub.3).
______________________________________
Claims (6)
1. Process for the manufacture of 6β-(3-substituted amino)-propionyloxy-7-deacetyl-forskolin derivatives of the general formula I ##STR8## wherein R1 and R2 each stands for hydrogen, alkyl, aryl, aralkyl or dialkylaminoalkyl; or
R1 and R2 together with the nitrogen to which they are attached form a heterocycle selected from the group consisting of morpholino, piperidino, pyrrolidino, piperazino, or homopiperidino, which may optionally be substituted at one or more positions by alkyl, alkoxy, hydroxyl, halogen or aryl and pharmaceutically acceptable salts thereof, which comprises
reacting in a one-pot reaction sequence 7-deacetyl forskolin of the formula II ##STR9## with a 3-haloproprionylhalide in the presence of an organic base and treating the 6β-(3-halopropionyloxy) derivative thus obtained with aqueous acetonitrile and an alkali hydroxide, followed by treating the 6β-(3-halopropionyloxy) derivative with an amine of the formula ##STR10## wherein R1 and R2 have the meaning given above and, if desired, converting the compounds of the formula I into their pharmaceutically acceptable salts.
2. Process as claimed in claim 1, wherein the amine is dimethylamine.
3. Process as claimed in claim 1, wherein the amine is piperidine.
4. Process as claimed in claim 1, wherein the amine is morpholine.
5. Process as claimed in claim 1, wherein the amine is N-methylpiperazine.
6. Process as claimed in claim 1, wherein the alkali hydroxide is sodium hydroxide.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP90114125 | 1990-07-24 | ||
| EP90114125 | 1990-07-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US5250682A true US5250682A (en) | 1993-10-05 |
Family
ID=8204250
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US07/733,812 Expired - Fee Related US5250682A (en) | 1990-07-24 | 1991-07-22 | Process for the preparation of 6-[3-substitutedaminopropionyl]-7-deacetylforskolin derivatives |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US5250682A (en) |
| EP (1) | EP0468443A1 (en) |
| JP (1) | JPH04297473A (en) |
| KR (1) | KR920002574A (en) |
| CN (1) | CN1059721A (en) |
| AU (1) | AU643045B2 (en) |
| CA (1) | CA2047940A1 (en) |
| CS (1) | CS231491A3 (en) |
| FI (1) | FI913507A (en) |
| HU (1) | HU208967B (en) |
| IE (1) | IE912593A1 (en) |
| IL (1) | IL98913A0 (en) |
| MX (1) | MX9100344A (en) |
| PL (1) | PL291200A1 (en) |
| RU (1) | RU2034840C1 (en) |
| YU (1) | YU128291A (en) |
| ZA (1) | ZA915762B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL98914A (en) * | 1990-07-24 | 1997-01-10 | Hoechst Ag | Process for the preparation of 6-(substituted aminopropionyl) derivatives of forskolin and intermediates used in such process |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0193132A2 (en) * | 1985-03-01 | 1986-09-03 | Hoechst-Roussel Pharmaceuticals Incorporated | Labdan-derivatives, a process for their preparation and their use as medicaments |
| US4639446A (en) * | 1984-12-14 | 1987-01-27 | Hoechst-Roussel Pharmaceuticals Inc. | Aminoacyllabdanes, pharmaceutical compositions and use |
| EP0217372A2 (en) * | 1985-10-02 | 1987-04-08 | Hoechst Aktiengesellschaft | Polyoxygenated labdane derivatives, process for their preparation and their use as medicaments |
| EP0222413A2 (en) * | 1985-11-15 | 1987-05-20 | Nippon Kayaku Kabushiki Kaisha | Novel forskolin derivatives |
| EP0294695A2 (en) * | 1987-06-06 | 1988-12-14 | Hoechst Aktiengesellschaft | New polyoxygenated labdane derivatives, a process for their preparation, and their use as medicaments |
| JPS649986A (en) * | 1987-07-01 | 1989-01-13 | Nippon Kayaku Kk | Novel phosphocholin derivative |
| US4883793A (en) * | 1988-05-09 | 1989-11-28 | Hoechst-Roussel Pharmaceuticals Inc. | Hydrazinocarbonyloxylabdanes for treating cardiac failure |
| US5041565A (en) * | 1988-05-09 | 1991-08-20 | Hoechst-Roussel Pharmaceuticals Inc. | Process for preparing hydrazinocarbonyloxylabdanes |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0447962A1 (en) * | 1990-03-17 | 1991-09-25 | Hoechst Aktiengesellschaft | Labdanes and process for their preparation |
| IL98914A (en) * | 1990-07-24 | 1997-01-10 | Hoechst Ag | Process for the preparation of 6-(substituted aminopropionyl) derivatives of forskolin and intermediates used in such process |
-
1991
- 1991-07-22 YU YU128291A patent/YU128291A/en unknown
- 1991-07-22 KR KR1019910012501A patent/KR920002574A/en not_active Application Discontinuation
- 1991-07-22 RU SU915001097A patent/RU2034840C1/en active
- 1991-07-22 US US07/733,812 patent/US5250682A/en not_active Expired - Fee Related
- 1991-07-22 IL IL98913A patent/IL98913A0/en unknown
- 1991-07-22 FI FI913507A patent/FI913507A/en unknown
- 1991-07-23 ZA ZA915762A patent/ZA915762B/en unknown
- 1991-07-23 PL PL29120091A patent/PL291200A1/en unknown
- 1991-07-23 EP EP91112324A patent/EP0468443A1/en not_active Withdrawn
- 1991-07-23 AU AU81209/91A patent/AU643045B2/en not_active Ceased
- 1991-07-23 CN CN91105007A patent/CN1059721A/en active Pending
- 1991-07-23 CS CS912314A patent/CS231491A3/en unknown
- 1991-07-23 CA CA002047940A patent/CA2047940A1/en not_active Abandoned
- 1991-07-23 MX MX9100344A patent/MX9100344A/en unknown
- 1991-07-23 IE IE259391A patent/IE912593A1/en unknown
- 1991-07-23 JP JP3182432A patent/JPH04297473A/en active Pending
- 1991-07-24 HU HU912490A patent/HU208967B/en not_active IP Right Cessation
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4639446A (en) * | 1984-12-14 | 1987-01-27 | Hoechst-Roussel Pharmaceuticals Inc. | Aminoacyllabdanes, pharmaceutical compositions and use |
| EP0193132A2 (en) * | 1985-03-01 | 1986-09-03 | Hoechst-Roussel Pharmaceuticals Incorporated | Labdan-derivatives, a process for their preparation and their use as medicaments |
| EP0217372A2 (en) * | 1985-10-02 | 1987-04-08 | Hoechst Aktiengesellschaft | Polyoxygenated labdane derivatives, process for their preparation and their use as medicaments |
| EP0222413A2 (en) * | 1985-11-15 | 1987-05-20 | Nippon Kayaku Kabushiki Kaisha | Novel forskolin derivatives |
| EP0294695A2 (en) * | 1987-06-06 | 1988-12-14 | Hoechst Aktiengesellschaft | New polyoxygenated labdane derivatives, a process for their preparation, and their use as medicaments |
| JPS649986A (en) * | 1987-07-01 | 1989-01-13 | Nippon Kayaku Kk | Novel phosphocholin derivative |
| US4883793A (en) * | 1988-05-09 | 1989-11-28 | Hoechst-Roussel Pharmaceuticals Inc. | Hydrazinocarbonyloxylabdanes for treating cardiac failure |
| US5041565A (en) * | 1988-05-09 | 1991-08-20 | Hoechst-Roussel Pharmaceuticals Inc. | Process for preparing hydrazinocarbonyloxylabdanes |
Non-Patent Citations (2)
| Title |
|---|
| Laurenza, A., et al., "Stimulation of Adenylate Cyclase by Water-Soluble Analogues of Forskolin", Molecular Pharmacology, 32:133-39 (1987). |
| Laurenza, A., et al., Stimulation of Adenylate Cyclase by Water Soluble Analogues of Forskolin , Molecular Pharmacology, 32:133 39 (1987). * |
Also Published As
| Publication number | Publication date |
|---|---|
| HU208967B (en) | 1994-02-28 |
| MX9100344A (en) | 1992-02-28 |
| CS231491A3 (en) | 1992-02-19 |
| HU912490D0 (en) | 1991-12-30 |
| RU2034840C1 (en) | 1995-05-10 |
| IL98913A0 (en) | 1992-07-15 |
| IE912593A1 (en) | 1992-01-29 |
| ZA915762B (en) | 1992-04-29 |
| FI913507A0 (en) | 1991-07-22 |
| CA2047940A1 (en) | 1992-01-25 |
| JPH04297473A (en) | 1992-10-21 |
| EP0468443A1 (en) | 1992-01-29 |
| CN1059721A (en) | 1992-03-25 |
| KR920002574A (en) | 1992-02-28 |
| FI913507A (en) | 1992-01-25 |
| AU8120991A (en) | 1992-03-26 |
| PL291200A1 (en) | 1992-03-09 |
| HUT58716A (en) | 1992-03-30 |
| AU643045B2 (en) | 1993-11-04 |
| YU128291A (en) | 1994-09-09 |
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